Thienopyridinone compounds and methods of treatment

ABSTRACT

The invention relates to 5-HT 4  receptor agonists and partial agonists. Thienopyridinone compounds and synthesis and uses thereof for treating diseases mediated directly or indirectly by 5-HT 4  receptors, are disclosed. Such conditions include Alzheimer&#39;s disease, cognition disorders, irritable bowel syndrome, Parkinson&#39;s disease, nausea, emesis, vomiting, prokinesia, gastroesophageal reflux disease, and nonulcer dyspepsia. Methods of preparation and novel intermediates and pharmaceutical salts thereof are also included.

RELATED APPLICATIONS

This application is related to U.S. patent application Ser. No.10/955,434, entitled “Thienopyridinone Compounds And Methods OfTreatment” and filed on Sep. 30, 2004, the entire contents of which isincorporated herein by reference.

FIELD OF THE INVENTION

The invention generally relates to the field of serotonin(5-hydroxytryptamine, or 5-HT) receptor modulators, e.g., 5-HT₄agonists, partial agonists, inverse agonists and antagonists, and moreparticularly to new thienopyridinone compounds, the synthesis and use ofthese compounds and their pharmaceutical compositions, e.g., in thetreatment, modulation and/or prevention of physiological conditionsassociated with serotonin action, such as in treating Alzheimer'sdisease, cognition disorders, irritable bowel syndrome, nausea, emesis,vomiting, prokinesia, gastroesophageal reflux disease and nonulcerdyspepsia.

BACKGROUND OF THE INVENTION

The serotonergic neural system of the brain has been shown to influencea variety of physiologic functions which manifest themselves in avariety of disorders such as Alzheimer's disease, cognition disorders,irritable bowel syndrome, nausea, emesis, vomiting, prokinesia,gastroesophageal reflux disease, nonulcer dyspepsia, depression,anxiety, urinary incontinence, migraine, arrhythmia, atrialfibrillation, ischemic stroke, gastritis, gastric emptying disorders,feeding disorders, gastrointestinal disorders, constipation, erectiledysfunction, and respiratory depression.

5-HT receptor modulators e.g., agonists, partial agonists, inverseagonists and antagonists, and/or selective serotonin reuptake inhibitors(SSRIs) such as fluoxetine, paroxetine, fluvoxamine, sertraline,lorazepam, imipramine, citalopram, and nortriptyline, may be used forthe treatment of the above conditions, as well as for vasodilation,smooth muscle contraction, bronchoconstriction, brain disorders such asvascular disorders such as angina and migraine; and neuropathologicaldisorders including Parkinson's disease and Alzheimer's disease. Theyalso intervene in the regulation of the cerebral circulation and thusrepresent effective agents for controlling migraine. They are alsosuitable for the prophylaxis and control of the effects of occurrencesof cerebral infarct (Apoplexia cerebri) such as stroke or cerebralischemia. They are also suitable for the control of disorders of theintestinal tract which are characterized by disturbances of theserotoninergic system and also by disturbances of the carbohydratemetabolism. They are suitable for the treatment of gastrointestinaldisorders including irritable bowel syndrome.

Tegaserod, an indazole carbazimidamide that acts as a 5-HT₄ agonist, hasbeen approved for irritable bowel syndrome (Buchheit el al. J. Med.Chem. 1995, 38, 2331-2338; Buchheit et. al., J. Med. Chem. 1995, 38,2326-2330).

The 5-HT₄ receptors represent a member of the family of receptors withseven transmembrane (7TM) domains coupled to a G-protein which ispositively coupled to adenylate cyclase. The 5-HT₄ receptors areexpressed in a wide variety of tissues, including the human brain andthe rodent brain, the human, dog, pig and rodent gastro-intestinaltract, and the pig and human heart. In the mammalian brain, the 5-HT₄receptors contribute to dopamine secretion and regulate learning andlong-term memory via the modification of acetylcholine release. In theperipheral tissues, the 5-HT₄ receptors have proven to regulategastro-intestinal tract motility, intestinal electrolyte secretion,adrenal secretion of corticosteroids, bladder contraction and atriumcontractility.

The 5-HT₄ receptors are involved in a wide variety of central andperipheral disorders, including cardiac arrhythmias andneurodegenerative disorders and more specifically Alzheimer's disease,cognition disorders, irritable bowel syndrome, nausea, emesis, vomiting,prokinesia, gastroesophageal reflux disease, nonulcer dyspepsia,depression, anxiety, urinary incontinence, migraine, arrhythmia, atrialfibrillation, ischemic stroke, gastritis, gastric emptying disorders,feeding disorders, gastrointestinal disorders, constipation, erectiledysfunction, and respiratory depression.

The development of 5-HT₄ receptor modulators, e.g., agonists, partialagonists, inverse agonists and antagonists, may have therapeuticapplications in the central nervous system for treating neuropsychiatricdisorders associated with a dysfunction of the central dopaminergicsystem, such as Parkinson's disease, or for treating amnesicdeficiencies as presented in patients suffering from Alzheimer'sdisease. Such medicines might also be useful for treating peripheraldisorders such as irritable bowel syndrome, gastroparesia, urinaryincontinence and cardiac arrhythmias. Selective, high affinity,metabolically stable 5-HT₄ receptor modulators that possess goodbioavailability, CNS penetration, and good pharmacokinetic properties,e.g., in vivo, are desirable.

SUMMARY OF THE INVENTION

The present invention relates to the discovery of new compounds whichare 5-HT₄ modulators, e.g., agonists, partial agonists, inverse agonistsand antagonists, that can be used for treating, preventing or curing5-HT-related conditions, such as Alzheimer's disease, cognitiondisorders, irritable bowel syndrome, Parkinson's disease, gastroparesia,urinary incontinence and cardiac arrhythmias.

In particular, it has been found that certain thienopyridinone compoundsare effective 5-HT₄ receptor partial agonists and/or full agonists andact as antagonists and/or SSRIs. In an embodiment, such compoundsinclude those having the formula

wherein

R₁ may be ethyl or isopropyl; and R₂ may be an optionally substitutedalkyl group such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, pentyl, methylcyclopropyl, isopropanol, phenylethyl; andpharmaceutically acceptable salts and/or esters thereof.

Compounds of the invention also include those having the formula

wherein

R₁ may be (C₁-C₈) branched or unbranched alkyl or alkenyl; a (C₁-C₈)substituted or unsubstituted carbocyclic ring; a substituted orunsubstituted aryl or heteroaryl ring; branched or unbranched haloalkyl(e.g., CF₃, CF₃—CH₂, CF₃—CF₂—); or a substituted or unsubstituted(CH₂)_(p)-aryl or (CH₂)_(p)-heteroaryl ring, where p is 1, 2, 3, or 4;and

R₂ may be an optionally substituted (C₁-C₆) branched or unbranchedalkyl, alkenyl, alkynyl, alkylhydroxy, alkylalkoxy, or alkylacyl group.Suitable substituents on R₂ include substituted or unsubstituted aryl;hydroxyl; (C₁-C₆) substituted or unsubstituted carbocyclic rings;substituted or unsubstituted (C₁-C₆)alkylhydroxy, substituted orunsubstituted (C₁-C₆)alkylalkoxy, substituted or unsubstituted(C₁-C₆)alkylamino, substituted or unsubstituted (C₁-C₆)alkylaminoacyl,substituted or unsubstituted (C₁-C₆)alkylaminoaryl.

Suitable R₂ groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl.

Compounds of the invention may also be 5-HT receptor modulators, e.g.,5-HT₄ receptor agonists, partial agonists, inverse agonists and/orantagonists.

In another embodiment compounds of the invention may also be 5-HTreceptor agonists, e.g., 5-HT₄ receptor agonists.

In another embodiment compounds of the invention may also be 5-HTreceptor partial agonists, e.g., 5-HT₄ receptor partial agonists.

In another embodiment compounds of the invention may also be 5-HTreceptor inverse agonists, e.g., 5-HT₄ receptor inverse agonists.

In another embodiment compounds of the invention may also be 5-HTreceptor antagonists, e.g., 5-HT₄ receptor antagonists.

Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formulae I or IIeffective to treat diseases such as Alzheimer's disease, cognitiondisorders, irritable bowel syndrome, Parkinson's disease, nausea,emesis, vomiting, prokinesia, gastroesophageal reflux disease, nonulcerdyspepsia, depression, anxiety, urinary incontinence, migraine,arrhythmia, atrial fibrillation, ischemic stroke, gastritis, gastricemptying disorders, feeding disorders, gastrointestinal disorders,constipation, erectile dysfunction, or respiratory depression, and apharmaceutically acceptable carrier.

Another aspect of the invention is a method for treating diseases suchas Alzheimer's disease, cognition disorders, irritable bowel syndrome,nausea, emesis, vomiting, prokinesia, gastroesophageal reflux disease,nonulcer dyspepsia, depression, anxiety, urinary incontinence, migraine,arrhythmia, atrial fibrillation, ischemic stroke, gastritis, gastricemptying disorders, feeding disorders, gastrointestinal disorders,constipation, erectile dysfunction, or respiratory depression in amammal such as a human comprising administering a therapeuticallyeffective amount of a compound according to Formulae I or II.

Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formulae I or IIeffective to treat Alzheimer's Disease in a mammal suffering therefrom,and a pharmaceutically acceptable carrier.

Another aspect of the invention is a method for treating Alzheimer'sDisease in a mammal such as a human comprising administering atherapeutically effective amount of a compound according to Formulae Ior II.

Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formulae I or IIeffective for memory enhancement in a mammal in need thereof, and apharmaceutically acceptable carrier.

Another aspect of the invention is a method for memory enhancement in amammal such as a human comprising administering a therapeuticallyeffective amount of a compound according to Formulae I or II.

Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formulae I or IIeffective in treating irritable bowel syndrome (IBS); and apharmaceutically acceptable carrier.

Another aspect of the invention is a method of treating irritable bowelsyndrome (IBS) comprising administering a therapeutically effectiveamount of a compound according to Formulae I or II.

Processes for preparing the compounds and novel intermediates are alsoincluded in the invention.

DETAILED DESCRIPTION OF THE INVENTION

The features and other details of the invention will now be moreparticularly described with reference to the accompanying drawings andpointed out in the claims. It will be understood that particularembodiments described herein are shown by way of illustration and not aslimitations of the invention. The principal features of this inventioncan be employed in various embodiments without departing from the scopeof the invention. All parts and percentages are by weight unlessotherwise specified.

Definitions

For convenience, certain terms used in the specification, examples, andappended claims are collected here.

“5-HT receptor modulator” or “5-HT modulator” includes compounds havingeffect at the 5-HT₁, 5-HT₂, 5-HT₃, 5-HT₄, 5-HT₅, 5-HT₆ or 5-HT₇receptors, including the subtypes of each receptor type, such as5-HT_(1A, B, C, D, E or F); 5-HT_(2A, B or C); h5-HT_(4a, b, c, d or e);and 5-HT_(5A or B). 5-HT modulators may be agonists, partial agonists,inverse agonists, or antagonists.

“Treating”, includes any effect, e.g., lessening, reducing, modulating,or eliminating, that results in the improvement of the condition,disease, disorder, etc.

“Alkyl” includes saturated aliphatic groups, including straight-chainalkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,octyl, nonyl, decyl), branched-chain alkyl groups (e.g., isopropyl,tert-butyl, isobutyl), cycloalkyl (e.g., alicyclic) groups (e.g.,cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkylsubstituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.“Alkyl” further includes alkyl groups which have oxygen, nitrogen,sulfur or phosphorous atoms replacing one or more hydrocarbon backbonecarbon atoms. In certain embodiments, a straight chain or branched chainalkyl has six or fewer carbon atoms in its backbone (e.g., C₁-C₆ forstraight chain, C₃-C₆ for branched chain), and more preferably four orfewer. Likewise, preferred cycloalkyls have from three to eight carbonatoms in their ring structure, and more preferably have five or sixcarbons in the ring structure. “C₁-C₆” includes alkyl groups containingone to six carbon atoms.

The term “alkyl” also includes both “unsubstituted alkyls” and“substituted alkyls”, the latter of which refers to alkyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example, alkyl,alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkylamino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Cycloalkyls can be further substituted, e.g.,with the substituents described above. An “alkylaryl” or an “aralkyl”moiety is an alkyl substituted with an aryl (e.g., phenylmethyl(benzyl)). “Alkyl” also includes the side chains of natural andunnatural amino acids.

“Aryl” includes groups with aromaticity, including 5- and 6-membered“unconjugated”, or single-ring, aromatic groups that may include fromzero to four heteroatoms, as well as “conjugated”, or multicyclic,systems with at least one aromatic ring. Examples of aryl groups includebenzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole,imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine,pyrazine, pyridazine, and pyrimidine, and the like. Furthermore, theterm “aryl” includes multicyclic aryl groups, e.g., tricyclic, bicyclic,e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole,benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline,isoquinoline, napthridine, indole, benzofuran, purine, benzofuran,deazapurine, or indolizine. Those aryl groups having heteroatoms in thering structure may also be referred to as “aryl heterocycles”,“heterocycles,” “heteroaryls” or “heteroaromatics”. The aromatic ringcan be substituted at one or more ring positions with such substituentsas described above, as for example, halogen, hydroxyl, alkoxy,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl,aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino(including alkylamino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Arylgroups can also be fused or bridged with alicyclic or heterocyclic ringswhich are not aromatic so as to form a multicyclic system (e.g.,tetralin, methylenedioxyphenyl).

“Alkenyl” includes unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but that contain atleast one double bond. For example, the term “alkenyl” includesstraight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl,pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), branched-chainalkenyl groups, cycloalkenyl (e.g., alicyclic) groups (e.g.,cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, andcycloalkyl or cycloalkenyl substituted alkenyl groups. The term“alkenyl” further includes alkenyl groups which include oxygen,nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbonbackbone carbons. In certain embodiments, a straight chain or branchedchain alkenyl group has six or fewer carbon atoms in its backbone (e.g.,C₂-C₆ for straight chain, C₃-C₆ for branched chain.) Likewise,cycloalkenyl groups may have from three to eight carbon atoms in theirring structure, and more preferably have five or six carbons in the ringstructure. The term “C₂-C₆” includes alkenyl groups containing two tosix carbon atoms.

The term “alkenyl” also includes both “unsubstituted alkenyls” and“substituted alkenyls”, the latter of which refers to alkenyl moietieshaving substituents replacing a hydrogen on one or more hydrocarbonbackbone carbon atoms. Such substituents can include, for example, alkylgroups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

“Alkynyl” includes unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but which containat least one triple bond. For example, “alkynyl” includes straight-chainalkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl,heptynyl, octynyl, nonynyl, decynyl), branched-chain alkynyl groups, andcycloalkyl or cycloalkenyl substituted alkynyl groups. The term“alkynyl” further includes alkynyl groups having oxygen, nitrogen,sulfur or phosphorous atoms replacing one or more hydrocarbon backbonecarbons. In certain embodiments, a straight chain or branched chainalkynyl group has six or fewer carbon atoms in its backbone (e.g., C₂-C₆for straight chain, C₃-C₆ for branched chain). The term “C₂-C₆” includesalkynyl groups containing two to six carbon atoms.

The term “alkynyl” also includes both “unsubstituted alkynyls” and“substituted alkynyls”, the latter of which refers to alkynyl moietieshaving substituents replacing a hydrogen on one or more hydrocarbonbackbone carbon atoms. Such substituents can include, for example, alkylgroups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

Unless the number of carbons is otherwise specified, “lower alkyl”includes an alkyl group, as defined above, but having from one to ten,more preferably from one to six, carbon atoms in its backbone structure.“Lower alkenyl” and “lower alkynyl” have chain lengths of, for example,2-5 carbon atoms.

“Acyl” includes compounds and moieties which contain the acyl radical(CH₃CO—) or a carbonyl group. “Substituted acyl” includes acyl groupswhere one or more of the hydrogen atoms are replaced by for example,alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

“Acylamino” includes moieties wherein an acyl moiety is bonded to anamino group. For example, the term includes alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido groups.

“Alkoxyalkyl”, “alkylaminoalkyl” and “thioalkoxyalkyl” include alkylgroups, as described above, which further include oxygen, nitrogen orsulfur atoms replacing one or more hydrocarbon backbone carbon atoms,e.g., oxygen, nitrogen or sulfur atoms.

The term “alkoxy” includes substituted and unsubstituted alkyl, alkenyl,and alkynyl groups covalently linked to an oxygen atom. Examples ofalkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy,and pentoxy groups. Examples of substituted alkoxy groups includehalogenated alkoxy groups. The alkoxy groups can be substituted withgroups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moieties. Examples of halogen substituted alkoxygroups include, but are not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

The terms “heterocyclyl” or “heterocyclic group” include closed ringstructures, e.g., 3- to 10-, or 4- to 7-membered rings, which includeone or more heteroatoms. Heterocyclyl groups can be saturated orunsaturated and include pyrrolidine, oxolane, thiolane, piperidine,piperizine, morpholine, lactones, lactams such as azetidinones andpyrrolidinones, sultams, sultones, and the like. The heterocyclic ringcan be substituted at one or more positions with such substituents asdescribed above, as for example, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl,alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (includingalkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, or an aromatic orheteroaromatic moiety.

The term “thiocarbonyl” or “thiocarboxy” includes compounds and moietieswhich contain a carbon connected with a double bond to a sulfur atom.

The term “ether” includes compounds or moieties which contain an oxygenbonded to two different carbon atoms or heteroatoms. For example, theterm includes “alkoxyalkyl” which refers to an alkyl, alkenyl, oralkynyl group covalently bonded to an oxygen atom which is covalentlybonded to another alkyl group.

The term “ester” includes compounds and moieties which contain a carbonor a heteroatom bound to an oxygen atom which is bonded to the carbon ofa carbonyl group. The term “ester” includes alkoxycarboxy groups such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynyl groups are asdefined above.

The term “thioether” includes compounds and moieties which contain asulfur atom bonded to two different carbon or heteroatoms. Examples ofthioethers include, but are not limited to alkthioalkyls,alkthioalkenyls, and alkthioalkynyls. The term “alkthioalkyls” includecompounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfuratom which is bonded to an alkyl group. Similarly, the term“alkthioalkenyls” and alkthioalkynyls” refer to compounds or moietieswherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atomwhich is covalently bonded to an alkynyl group.

The term “hydroxy” or “hydroxyl” includes groups with an —OH or —O⁻.

The term “halogen” includes fluorine, bromine, chlorine, iodine, etc.The term “perhalogenated” generally refers to a moiety wherein allhydrogens are replaced by halogen atoms.

“Heteroatom” includes atoms of any element other than carbon orhydrogen. Examples of heteroatoms include nitrogen, oxygen, sulfur andphosphorus.

It will be noted that the structure of some of the compounds of theinvention includes asymmetric carbon atoms. It is to be understoodaccordingly that the isomers arising from such asymmetry (e.g., allenantiomers and diastereomers) are included within the scope of theinvention, unless indicated otherwise. Such isomers can be obtained insubstantially pure form by classical separation techniques and bystereochemically controlled synthesis. Furthermore, the structures andother compounds and moieties discussed in this application also includeall tautomers thereof. Alkenes can include either the E- or Z-geometry,where appropriate.

“Combination therapy” (or “co-therapy”) includes the administration of a5-HT modulator of the invention and at least a second agent as part of aspecific treatment regimen intended to provide the beneficial effectfrom the co-action of these therapeutic agents. The beneficial effect ofthe combination includes, but is not limited to, pharmacokinetic orpharmacodynamic co-action resulting from the combination of therapeuticagents. Administration of these therapeutic agents in combinationtypically is carried out over a defined time period (usually minutes,hours, days or weeks depending upon the combination selected).“Combination therapy” may, but generally is not, intended to encompassthe administration of two or more of these therapeutic agents as part ofseparate monotherapy regimens that incidentally and arbitrarily resultin the combinations of the present invention. “Combination therapy” isintended to embrace administration of these therapeutic agents in asequential manner, that is, wherein each therapeutic agent isadministered at a different time, as well as administration of thesetherapeutic agents, or at least two of the therapeutic agents, in asubstantially simultaneous manner. Substantially simultaneousadministration can be accomplished, for example, by administering to thesubject a single capsule having a fixed ratio of each therapeutic agentor in multiple, single capsules for each of the therapeutic agents.Sequential or substantially simultaneous administration of eachtherapeutic agent can be effected by any appropriate route including,but not limited to, oral routes, intravenous routes, intramuscularroutes, and direct absorption through mucous membrane tissues. Thetherapeutic agents can be administered by the same route or by differentroutes. For example, a first therapeutic agent of the combinationselected may be administered by intravenous injection while the othertherapeutic agents of the combination may be administered orally.Alternatively, for example, all therapeutic agents may be administeredorally or all therapeutic agents may be administered by intravenousinjection. The sequence in which the therapeutic agents are administeredis not narrowly critical. “Combination therapy” also can embrace theadministration of the therapeutic agents as described above in furthercombination with other biologically active ingredients and non-drugtherapies (e.g., surgery or radiation treatment.) Where the combinationtherapy further comprises a non-drug treatment, the non-drug treatmentmay be conducted at any suitable time so long as a beneficial effectfrom the co-action of the combination of the therapeutic agents andnon-drug treatment is achieved. For example, in appropriate cases, thebeneficial effect is still achieved when the non-drug treatment istemporally removed from the administration of the therapeutic agents,perhaps by days or even weeks.

An “anionic group,” as used herein, refers to a group that is negativelycharged at physiological pH. Preferred anionic groups includecarboxylate, sulfate, sulfonate, sulfinate, sulfamate, tetrazolyl,phosphate, phosphonate, phosphinate, or phosphorothioate or functionalequivalents thereof. “Functional equivalents” of anionic groups areintended to include bioisosteres, e.g., bioisosteres of a carboxylategroup. Bioisosteres encompass both classical bioisosteric equivalentsand non-classical bioisosteric equivalents. Classical and non-classicalbioisosteres are known in the art (see, e.g., Silverman, R. B. TheOrganic Chemistry of Drug Design and Drug Action, Academic Press, Inc.:San Diego, Calif., 1992, pp. 19-23). A particularly preferred anionicgroup is a carboxylate.

The term “heterocyclic group” is intended to include closed ringstructures in which one or more of the atoms in the ring is an elementother than carbon, for example, nitrogen, or oxygen or sulfur.Heterocyclic groups can be saturated or unsaturated and heterocyclicgroups such as pyrrole and furan can have aromatic character. Theyinclude fused ring structures such as quinoline and isoquinoline. Otherexamples of heterocyclic groups include pyridine and purine.Heterocyclic groups can also be substituted at one or more constituentatoms with, for example, a halogen, a lower alkyl, a lower alkenyl, alower alkoxy, a lower alkylthio, a lower alkylamino, a loweralkylcarboxyl, a nitro, a hydroxyl, —CF₃, —CN, or the like.

Compounds of the invention may generally be used in the treatment orprophylaxis of gastrointestinal disorders, cardiovascular disorders andCNS disorders. They are of potential interest in the treatment ofirritable bowel syndrome (IBS), in particular the diarrhea aspects ofIBS, i.e., these compounds block the ability of 5-HT to stimulate gutmotility via activation of enteric neurons. In animal models of IBS,this can be conveniently measured as a reduction of the rate ofdefecation. They are also of potential use in the treatment of urinaryincontinence which is often associated with IBS. They may also be ofpotential use in other gastrointestinal disorders, such as thoseassociated with upper gut motility, and as anti-emetics. In particular,they are of potential use in the treatment of the nausea and gastricsymptoms of gastro-esophageal reflux disease and dyspepsia. Anti-emeticactivity is determined in known animal models ofcytotoxic-agent/radiation induced emesis.

Specific cardiac 5-HT₄ receptor antagonists which prevent atrialfibrillation and other atrial arrhythmias associated with 5-HT, wouldalso be expected to reduce occurrence of stroke (see A. J. Kaumann 1990,Naumyn-Schmiedeberg's Arch. Pharmacol. 342, 619-622, for appropriateanimal test method).

The invention thus further provides a method of treatment of irritablebowel syndrome, gastro-esophageal reflux disease, dyspepsia, atrialarrhythmias, stroke and ischemic stroke, anxiety, migraine, Alzheimer'sdisease, cognition disorders, irritable bowel syndrome, Parkinson'sdisease, nausea, emesis, vomiting, prokinesia, gastroesophageal refluxdisease, nonulcer dyspepsia, depression, anxiety, urinary incontinence,atrial fibrillation, gastritis, gastric emptying disorders, feedingdisorders, gastrointestinal disorders, constipation, erectiledysfunction and/or respiratory depression in mammals, such as humans,which comprises the administration of an effective amount of a compoundof the formula (I) or a pharmaceutically acceptable salt thereof. Inparticular, the method comprises treatment of IBS or atrial arrhythmiasand stroke.

The compounds of the invention have a high affinity and specificity for5-HT₄ serotoninergic receptors. They are able to stimulate or inhibit,either at central or peripheral level, those effects mediated by theactivation of this receptor subtype. Therefore, the compounds of theinvention may be defined as novel agonists or partial agonists,antagonists or inverse agonists in vitro and in vivo of 5-HT₄ receptors.5-HT₄ receptors belong to the family of serotoninergic receptors andthey are among those more recently discovered, pharmacologicallycharacterized and cloned. After the first identification in discreteareas of guinea-pig CNS, the 5-HT₄ serotoninergic receptors have beenlocalized also in other districts, either central or peripheral (ileum,atrium, esophagus, colon, urinary bladder and adrenal glands) ofdifferent species, including humans. The presence of these receptors indifferent organs and tissues, make it possible that compounds able toblock the effects of their hyperstimulation, may be advantageously usedin the treatment and in the prophylaxis of different pathologicalsituations.

Thus, for example, since the stimulation of 5-HT₄ atrial cardiacreceptors, besides causing inotropic and chronotropic positive effects,is responsible for arrhythmias observed in some experimental conditions,antagonists to these receptors may be used in the specific treatment ofcardiac rhythm disorders, such as atrial fibrillation and other types ofarrhythmias. In the gastro-intestinal tract, since the 5-HT₄ receptorsmediate the prokinetic and secretory action of serotonin, it can besuggested the use of 5-HT₄ antagonists in the treatment of disordersconnected to an altered intestinal motility or secretion such as IBS,more particularly in those forms of IBS combined to diarrheic states.The presence of 5-HT₄ receptors in the central nervous system of eitherrat or humans may be limited to defined areas such as hippocampus,frontal cortex, basal ganglia and limbic structures. Compounds able tocontrol an altered stimulation of the 5-HT₄ receptors in the CNS maytherefore be used in the psychiatric and neurological fields such asAlzheimer's disease, cognition disorders, irritable bowel syndrome,Parkinson's disease, irritable bowel syndrome, nausea, emesis, vomiting,prokinesia, gastroesophageal reflux disease, nonulcer dyspepsia,depression, anxiety, urinary incontinence, migraine, arrhythmia, atrialfibrillation, ischemic stroke, gastritis, gastric emptying disorders,feeding disorders, gastrointestinal disorders, constipation, erectiledysfunction, or respiratory depression. Moreover, since it has beendescribed that 5-HT₄ receptors partially mediate the effect of 5-HT incontrolling ethanol intake, 5-HT₄ antagonists might be useful in thetreatment of alcohol abuse. 5-HT₄ receptors are also involved in thecontrol of other functions of the genitourinary and adrenal glandssystem, where they seem to mediate the release of steroidal hormones.Consequently, pathologies characterized by an altered secretion ofhormones or urinary incontinence might be also treated with compoundsable to block the 5-HT₄ receptors.

The present invention relates to the discovery of new compounds whichare 5-HT modulators, e.g., agonists, partial agonists, antagonists,and/or SSRIs, that can be used for treating, preventing or curing5-HT-related conditions. In particular, it has been found that certainthienopyridinone compounds are effective 5-HT receptor modulators, morespecifically 5-HT₄, 5-HT_(4a) and 5-HT_(4e) receptor modulators and/orSSRIs.

Compounds of the invention include those having the formula

wherein

R₁ may be ethyl or isopropyl; and R₂ may be an optionally substitutedalkyl group such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, pentyl, methylcyclopropyl, isopropanol, phenylethyl; andpharmaceutically acceptable salts and/or esters thereof.

Compounds of the invention also include those having the formula

wherein

R₁ may be (C₁-C₈) branched or unbranched alkyl or alkenyl; a (C₁-C₈)substituted or unsubstituted carbocyclic ring; a substituted orunsubstituted aryl or heteroaryl ring; branched or unbranched haloalkyl(e.g., CF₃, CF₃—CH₂, CF₃—CF₂—); or a substituted or unsubstituted(CH₂)_(p)-aryl or (CH₂)_(p)-heteroaryl ring, where p is 1, 2, 3, or 4;and

R₂ may be an optionally substituted (C₁-C₆) branched or unbranchedalkyl, alkenyl, alkynyl, alkylhydroxy, alkylalkoxy, or alkylacyl group.Suitable substituents on R₂ include substituted or unsubstituted aryl;hydroxyl; (C₁-C₆) substituted or unsubstituted carbocyclic rings;substituted or unsubstituted (C₁-C₆)alkylhydroxy, substituted orunsubstituted (C₁-C₆)alkylalkoxy, substituted or unsubstituted(C₁-C₆)alkylamino, substituted or unsubstituted (C₁-C₆)alkylaminoacyl,substituted or unsubstituted (C₁-C₆)alkylaminoaryl.

Suitable R₂ groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl.

Compounds of the invention may also be 5-HT receptor antagonists, e.g.,5-HT₄ receptor antagonists.

In another embodiment compounds of the invention may also be 5-HTreceptor partial agonists, e.g., 5-HT₄, 5-HT_(4a) 5-HT_(4e) receptorpartial agonists.

In another embodiment compounds of the invention may also be 5-HTreceptor agonists, e.g., 5-HT₄ receptor agonists.

In another embodiment compounds of the invention may also be 5-HTreceptor inverse agonists, e.g., 5-HT₄ receptor inverse agonists.

Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formulae I or IIeffective to treat diseases of the central nervous system in a mammalsuffering therefrom, and a pharmaceutically acceptable carrier.

Another aspect of the invention is a method for treating diseases of thecentral nervous system in a mammal such as a human comprisingadministering a therapeutically effective amount of a compound accordingto Formulae I or II.

Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formulae I or Heffective to treat Alzheimer's Disease in a mammal suffering therefrom,and a pharmaceutically acceptable carrier.

Another aspect of the invention is a method for treating Alzheimer'sDisease in a mammal such as a human comprising administering atherapeutically effective amount of a compound according to Formulae Ior II.

Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formulae I or IIeffective for memory enhancement in a mammal in need thereof, and apharmaceutically acceptable carrier.

Another aspect of the invention is a method for memory enhancement in amammal such as a human comprising administering a therapeuticallyeffective amount of a compound according to Formulae I or II.

Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formulae I or IIeffective in treating irritable bowel syndrome (IBS); and apharmaceutically acceptable carrier.

Another aspect of the invention is a method of treating irritable bowelsyndrome (IBS) comprising administering a therapeutically effectiveamount of a compound according to Formulae I or II.

Processes for preparing the compounds and novel intermediates are alsoincluded in the invention.

The compounds of the invention are valuable for treating a wide varietyof clinical conditions which are characterized by serotonin excess orabsence, e.g., serotonergic hypofunction or hyperfunction. Suchconditions include schizophrenia and other psychotic disorders, forexample, schizophrenic disorders, schizoaffective disorders, delusionaldisorders, brief psychotic disorders, shared psychotic disorders andpsychotic disorders with delusions or hallucinations; gastrointestinaldisorders like Crohn's disease, eating disorders, neuralgia, andaddiction disorders; obsessive compulsive disorders, panic disorders,sexual dysfunctions caused by the central nervous system anddisturbances in sleep and the absorption of food, alcoholism, pain,memory deficits, unipolar depression, dysthymia, bipolar depression,treatment-resistant depression, depression in the medically ill, panicdisorder, obsessive-compulsive disorder, eating disorders, socialphobia, premenstrual dysphoric disorder, mood disorders, such asdepression or more particularly depressive disorders, for example,single episodic or recurrent major depressive disorders and dysthymicdisorders, or bipolar disorders, for example, bipolar I disorder,bipolar II disorder and cyclothymic disorder; anxiety disorders, such aspanic disorder with or without agoraphobia, agoraphobia without historyof panic disorder, specific phobias, e.g., specific animal phobias,social phobias, stress disorders including post-traumatic stressdisorder and acute stress disorder, and generalized anxiety disorders;delirium, dementia, and amnestic and other cognitive orneurodegenerative disorders, such as Alzheimer's disease, seniledementia, dementia of the Alzheimer's type, vascular dementia, and otherdementias, for example, due to HIV disease, head trauma, Parkinson'sdisease, Huntington's disease, Pick's disease, Creutzfeldt-Jakobdisease, or due to multiple etiologies; Parkinson's disease and otherextra-pyramidal movement disorders such as medication-induced movementdisorders, for example, neuroleptic-induced parkinsonism, neurolepticmalignant syndrome, neuroleptic-induced acute dystonia,neuroleptic-induced acute akathisia, neuroleptic-induced tardivedyskinesia and medication-induced postural tremor; substance-relateddisorders arising from the use of alcohol, amphetamines (oramphetamine-like substances) caffeine, cannabis, cocaine, hallucinogens,inhalants and aerosol propellants, nicotine, opioids, phenylglycidinederivatives, sedatives, hypnotics, and anxiolytics, whichsubstance-related disorders include dependence and abuse, intoxication,withdrawal, intoxication delirium, withdrawal delirium, persistingdementia, psychotic disorders, mood disorders, anxiety disorders, sexualdysfunction and sleep disorders; epilepsy; Down's syndrome;demyelinating diseases such as MS and ALS and other neuropathologicaldisorders such as peripheral neuropathy, for example diabetic andchemotherapy-induced neuropathy, and postherpetic neuralgia, trigeminalneuralgia, segmental or intercostal neuralgia and other neuralgias; andcerebral vascular disorders due to acute or chronic cerebrovasculardamage such as cerebral infarction, subarachnoid hemorrhage or cerebraledema.

Compounds of the invention may be used for the treatment of the aboveconditions, as well as for vasodilation, smooth muscle contraction,bronchoconstriction, brain disorders such as vascular disorders, e.g.,blood flow disorders caused by vasodilation and vasospastic diseasessuch as angina, vascular headache, migraine and Reynaud's disease;pulmonary hypertension and systemic hypertension; and neuropathologicaldisorders including Parkinson's disease and Alzheimer's disease;modulation of the cardiovascular system; prophylaxis and control of theeffects of occurrences of cerebral infarct (Apoplexia cerebri) such asstroke or cerebral ischemia; and for the control of disorders of theintestinal tract which are characterized by disturbances of theserotoninergic system and also by disturbances of the carbohydratemetabolism.

The compounds may also be useful in treating a variety of otherconditions including stress-related somatic disorders; reflexsympathetic dystrophy such as shoulder/hand syndrome; disorders ofbladder function such as cystitis, bladder detrusor hyper-reflexia andincontinence; and pain or nociception attributable to or associated withany of the foregoing conditions, especially pain transmission inmigraine.

For treating certain conditions it may be desirable to employ thecompounds of the invention in conjunction with another pharmacologicallyactive agent. The compounds of the invention may be presented togetherwith another therapeutic agent as a combined preparation forsimultaneous, separate or sequential use. Such combined preparations maybe, for example, in the form of a twin pack.

A further aspect of the invention comprises compounds of the inventionin combination with a or another 5-HT antagonist and/or SSRI, e.g., a5-HT₃ antagonist such as ondansetron, granisetron, tropisetron orzatisetron. Additionally, the compounds of the invention may beadministered in combination with an anti-inflammatory corticosteroid,such as dexamethasone. Furthermore, the compounds of the invention maybe administered in combination with a chemotherapeutic agent such as analkylating agent, anti-metabolite, mitotic inhibitor or cytotoxicantibiotic, as described above. In general, the currently availabledosage forms of the known therapeutic agents for use in suchcombinations will be suitable.

According to a further or alternative aspect, the invention providescompounds of the invention for use in the manufacture of a medicamentfor the treatment or prevention of physiological disorders associatedwith serotonin excess or absence, e.g., serotonergic hypofunction orhyperfunction.

The invention also provides methods for treating or preventingphysiological disorders associated with serotonin excess or absence,e.g., serotonergic hypofunction or hyperfunction, which method comprisesadministration to a patient in need thereof of an effective amount of acompound of the invention or a composition comprising a compound of theinvention.

For treating or preventing migraine, the compounds of the invention maybe used in conjunction with other anti-migraine agents, such asergotamines or 5-HT₁ agonists, especially sumatriptan or rizatriptan.Likewise, for treating behavioral hyperalgesia, the compounds of theinvention may be used in conjunction with an antagonist of N-methylD-aspartate (NMDA), such as dizocilpine.

The compounds of the invention and the other pharmacologically activeagent may be administered to a patient simultaneously, sequentially orin combination. It will be appreciated that when using a combination ofthe invention, the compound of the invention and the otherpharmacologically active agent may be in the same pharmaceuticallyacceptable carrier and therefore administered simultaneously. They maybe in separate pharmaceutical carriers such as conventional oral dosageforms which are taken simultaneously. The term “combination” furtherrefers to the case where the compounds are provided in separate dosageforms and are administered sequentially.

The compounds of the invention may be administered to patients (animalsand humans) in need of such treatment in dosages that will provideoptimal pharmaceutical efficacy. It will be appreciated that the doserequired for use in any particular application will vary from patient topatient, not only with the particular compound or composition selected,but also with the route of administration, the nature of the conditionbeing treated, the age and condition of the patient, concurrentmedication or special diets then being followed by the patient, andother factors which those skilled in the art will recognize, with theappropriate dosage ultimately being at the discretion of the attendantphysician.

In the treatment of a condition associated with a serotonin excess orabsence, e.g., serotonergic hypofunction or hyperfunction, anappropriate dosage level will generally be about 0.001 to 50 mg per kgpatient body weight per day, which may be administered in single ormultiple doses. Preferably, the dosage level will be about 0.01 to about25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day.For example, in the treatment or prevention of a disorder of the centralnervous system, a suitable dosage level is about 0.001 to 10 mg/kg perday, preferably about 0.005 to 5 mg/kg per day, and especially about0.01 to 1 mg/kg per day. The compounds may be administered on a regimenof 1 to 4 times per day, preferably once or twice per day.

It will be appreciated that the amount of the compound of the inventionrequired for use in any treatment will vary not only with the particularcompounds or composition selected but also with the route ofadministration, the nature of the condition being treated, and the ageand condition of the patient, and will ultimately be at the discretionof the attendant physician.

The compositions and combination therapies of the invention may beadministered in combination with a variety of pharmaceutical excipients,including stabilizing agents, carriers and/or encapsulation formulationsas described herein.

Aqueous compositions of the present invention comprise an effectiveamount of the peptides of the invention, dissolved or dispersed in apharmaceutically acceptable carrier or aqueous medium.

“Pharmaceutically or pharmacologically acceptable” include molecularentities and compositions that do not produce an adverse, allergic orother untoward reaction when administered to an animal, or a human, asappropriate. “Pharmaceutically acceptable carrier” includes any and allsolvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutical active substances is well knownin the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

For human administration, preparations should meet sterility,pyrogenicity, general safety and purity standards as required by FDAOffice of Biologics standards.

The compositions and combination therapies of the invention will thengenerally be formulated for parenteral administration, e.g., formulatedfor injection via the intravenous, intramuscular, subcutaneous,intralesional, or even intraperitoneal routes. The preparation of anaqueous composition that contains a composition of the invention or anactive component or ingredient will be known to those of skill in theart in light of the present disclosure. Typically, such compositions canbe prepared as injectables, either as liquid solutions or suspensions;solid forms suitable for using to prepare solutions or suspensions uponthe addition of a liquid prior to injection can also be prepared; andthe preparations can also be emulsified.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions; formulations including sesame oil,peanut oil or aqueous propylene glycol; and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms, such as bacteria and fungi.

Solutions of active compounds as free base or pharmacologicallyacceptable salts can be prepared in water suitably mixed with asurfactant, such as hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofand in oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms.

Therapeutic or pharmacological compositions of the present inventionwill generally comprise an effective amount of the component(s) of thecombination therapy, dissolved or dispersed in a pharmaceuticallyacceptable medium. Pharmaceutically acceptable media or carriers includeany and all solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents and the like.The use of such media and agents for pharmaceutical active substances iswell known in the art. Supplementary active ingredients can also beincorporated into the therapeutic compositions of the present invention.

The preparation of pharmaceutical or pharmacological compositions willbe known to those of skill in the art in light of the presentdisclosure. Typically, such compositions may be prepared as injectables,either as liquid solutions or suspensions; solid forms suitable forsolution in, or suspension in, liquid prior to injection; as tablets orother solids for oral administration; as time release capsules; or inany other form currently used, including cremes, lotions, mouthwashes,inhalants and the like.

Sterile injectable solutions are prepared by incorporating the activecompounds in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

The preparation of more, or highly, concentrated solutions forintramuscular injection is also contemplated. In this regard, the use ofDMSO as solvent is preferred as this will result in extremely rapidpenetration, delivering high concentrations of the active compound(s) oragent(s) to a small area.

The use of sterile formulations, such as saline-based washes, bysurgeons, physicians or health care workers to cleanse a particular areain the operating field may also be particularly useful. Therapeuticformulations in accordance with the present invention may also bereconstituted in the form of mouthwashes, or in conjunction withantifungal reagents. Inhalant forms are also envisioned. The therapeuticformulations of the invention may also be prepared in forms suitable fortopical administration, such as in cremes and lotions.

Suitable preservatives for use in such a solution include benzalkoniumchloride, benzethonium chloride, chlorobutanol, thimerosal and the like.Suitable buffers include boric acid, sodium and potassium bicarbonate,sodium and potassium borates, sodium and potassium carbonate, sodiumacetate, sodium biphosphate and the like, in amounts sufficient tomaintain the pH at between about pH 6 and pH 8, and preferably, betweenabout pH 7 and pH 7.5. Suitable tonicity agents are dextran 40, dextran70, dextrose, glycerin, potassium chloride, propylene glycol, sodiumchloride, and the like, such that the sodium chloride equivalent of theophthalmic solution is in the range 0.9 plus or minus 0.2%. Suitableantioxidants and stabilizers include sodium bisulfite, sodiummetabisulfite, sodium thiosulfite, thiourea and the like. Suitablewetting and clarifying agents include polysorbate 80, polysorbate 20,poloxamer 282 and tyloxapol. Suitable viscosity-increasing agentsinclude dextran 40, dextran 70, gelatin, glycerin,hydroxyethylcellulose, hydroxmethylpropylcellulose, lanolin,methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol,polyvinylpyrrolidone, carboxymethylcellulose and the like.

Upon formulation, therapeutics will be administered in a mannercompatible with the dosage formulation, and in such amount as ispharmacologically effective. The formulations are easily administered ina variety of dosage forms, such as the type of injectable solutionsdescribed above, but drug release capsules and the like can also beemployed.

In this context, the quantity of active ingredient and volume ofcomposition to be administered depends on the host animal to be treated.Precise amounts of active compound required for administration depend onthe judgment of the practitioner and are peculiar to each individual.

A minimal volume of a composition required to disperse the activecompounds is typically utilized. Suitable regimes for administration arealso variable, but would be typified by initially administering thecompound and monitoring the results and then giving further controlleddoses at further intervals. For example, for parenteral administration,a suitably buffered, and if necessary, isotonic aqueous solution wouldbe prepared and used for intravenous, intramuscular, subcutaneous oreven intraperitoneal administration. One dosage could be dissolved in 1ml of isotonic NaCl solution and either added to 1000 ml ofhypodermolysis fluid or injected at the proposed site of infusion, (seefor example, Remington's Pharmaceutical Sciences 15th Edition, pages1035-1038 and 1570-1580).

In certain embodiments, active compounds may be administered orally.This is contemplated for agents which are generally resistant, or havebeen rendered resistant, to proteolysis by digestive enzymes. Suchcompounds are contemplated to include chemically designed or modifiedagents; dextrorotatory peptides; and peptide and liposomal formulationsin time release capsules to avoid peptidase and lipase degradation.

Pharmaceutically acceptable salts include acid addition salts and whichare formed with inorganic acids such as, for example, hydrochloric,hydrobromic, boric, phosphoric, sulfuric acids or phosphoric acids, orsuch organic acids as acetic, oxalic, tartaric, maleic, fumaric, citric,succinic, mesylic, mandelic, succinic, benzoic, ascorbic,methanesulphonic, a-keto glutaric, a-glycerophosphoric,glucose-1-phosphoric acids and the like. Salts formed with the freecarboxyl groups can also be derived from inorganic bases such as, forexample, sodium, potassium, ammonium, calcium, magnesium, or ferrichydroxides, and such organic bases as isopropylamine, trimethylamine,histidine, procaine and the like. Other examples of pharmaceuticallyacceptable salts include quaternary derivatives of the compounds offormula (1) such as the compounds quaternized by compounds R_(x)-Twherein R_(x) is C₁₋₆ alkyl, phenyl-C₁₋₆ alkyl or C₅₋₇ cycloalkyl, and Tis a radical corresponding to an anion of an acid. Suitable examples ofR_(x) include methyl, ethyl and n- and iso-propyl; and benzyl andphenethyl. Suitable examples of T include halide, e.g., chloride,bromide or iodide. Yet other examples of pharmaceutically acceptablesalts also include internal salts such as N-oxides.

The carrier can also be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), suitable mixturesthereof, and vegetable oils. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin, by the maintenanceof the required particle size in the case of dispersion and by the useof surfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions can be brought about by the use in thecompositions of agents delaying absorption, for example, aluminummonostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompounds in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

The preparation of more, or highly, concentrated solutions for directinjection is also contemplated, where the use of DMSO as solvent isenvisioned to result in extremely rapid penetration, delivering highconcentrations of the active agents to a small area.

Upon formulation, solutions will be administered in a manner compatiblewith the dosage formulation and in such amount as is therapeuticallyeffective. The formulations are easily administered in a variety ofdosage forms, such as the type of injectable solutions described above,but drug release capsules and the like can also be employed.

For parenteral administration in an aqueous solution, for example, thesolution should be suitably buffered if necessary and the liquid diluentfirst rendered isotonic with sufficient saline or glucose. Theseparticular aqueous solutions are especially suitable for intravenous,intramuscular, subcutaneous and intraperitoneal administration. In thisconnection, sterile aqueous media which can be employed will be known tothose of skill in the art in light of the present disclosure.

In addition to the compounds formulated for parenteral administration,such as intravenous or intramuscular injection, other pharmaceuticallyacceptable forms include, e.g., tablets or other solids for oraladministration; liposomal formulations; time-release capsules; and anyother form currently used, including cremes.

Additional formulations suitable for other modes of administrationinclude suppositories. For suppositories, traditional binders andcarriers may include, for example, polyalkylene glycols ortriglycerides; such suppositories may be formed from mixtures containingthe active ingredient in the range of 0.5% to 10%, preferably 1%-2%.

Oral formulations include such normally employed excipients as, forexample, pharmaceutical grades of mannitol, lactose, starch, magnesiumstearate, sodium saccharine, cellulose, magnesium carbonate and thelike. These compositions take the form of solutions, suspensions,tablets, pills, capsules, sustained release formulations or powders.

In certain defined embodiments, oral pharmaceutical compositions willcomprise an inert diluent or assimilable edible carrier, or they may beenclosed in hard or soft shell gelatin capsule, or they may becompressed into tablets, or they may be incorporated directly with thefood of the diet. For oral therapeutic administration, the activecompounds may be incorporated with excipients and used in the form ofingestible tablets, buccal tables, troches, capsules, elixirs,suspensions, syrups, wafers, and the like. Such compositions andpreparations should contain at least 0.1% of active compound. Thepercentage of the compositions and preparations may, of course, bevaried and may conveniently be between about 2 to about 75% of theweight of the unit, or preferably between 25-60%. The amount of activecompounds in such therapeutically useful compositions is such that asuitable dosage will be obtained.

The tablets, troches, pills, capsules and the like may also contain thefollowing: a binder, as gum tragacanth, acacia, cornstarch, or gelatin;excipients, such as dicalcium phosphate; a disintegrating agent, such ascorn starch, potato starch, alginic acid and the like; a lubricant, suchas magnesium stearate; and a sweetening agent, such as sucrose, lactoseor saccharin may be added or a flavoring agent, such as peppermint, oilof wintergreen, or cherry flavoring. When the dosage unit form is acapsule, it may contain, in addition to materials of the above type, aliquid carrier. Various other materials may be present as coatings or tootherwise modify the physical form of the dosage unit. For instance,tablets, pills, or capsules may be coated with shellac, sugar or both. Asyrup of elixir may contain the active compounds sucrose as a sweeteningagent methyl and propylparabensas preservatives, a dye and flavoring,such as cherry or orange flavor.

The pharmaceutical compositions of this invention may be used in theform of a pharmaceutical preparation, for example, in solid, semisolidor liquid form, which contains one or more of the compound of theinvention, as an active ingredient, in admixture with an organic orinorganic carrier or excipient suitable for external, enteral orparenteral applications. The active ingredient may be compounded, forexample, with the usual non-toxic, pharmaceutically acceptable carriersfor tablets, pellets, capsules, suppositories, solutions, emulsions,suspensions, and any other form suitable for use. The carriers which canbe used are water, glucose, lactose, gum acacia, gelatin, mannitol,starch paste, magnesium trisilicate, talc, corn starch, keratin,colloidal silica, potato starch, urea and other carriers suitable foruse in manufacturing preparations, in solid, semisolid, or liquid form,and in addition auxiliary, stabilizing, thickening and coloring agentsand perfumes may be used. The active object compound is included in thepharmaceutical composition in an amount sufficient to produce thedesired effect upon the process or condition of the disease.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g., conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g., water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the invention, or a non-toxic pharmaceutically acceptablesalt thereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules. This solid preformulation composition is thensubdivided into unit dosage forms of the type described above containingfrom 0.1 to about 500 mg of the active ingredient of the invention. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the compositions of the invention may beincorporated for administration orally or by injection include aqueoussolution, suitably flavored syrups, aqueous or oil suspensions, andemulsions with acceptable oils such as cottonseed oil, sesame oil,coconut oil or peanut oil, or with a solubilizing or emulsifying agentsuitable for intravenous use, as well as elixirs and similarpharmaceutical vehicles. Suitable dispersing or suspending agents foraqueous suspensions include synthetic and natural gums such astragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone or gelatin.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably sterile pharmaceutically acceptable solvents may be nebulizedby use of inert gases. Nebulized solutions may be breathed directly fromthe nebulizing device or the nebulizing device may be attached to a facemask, tent or intermittent positive pressure breathing machine.Solution, suspension or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

For treating clinical conditions and diseases noted above, the compoundof this invention may be administered orally, topically, parenterally,by inhalation spray or rectally in dosage unit formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvantsand vehicles. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques.

Methods for preparing the compounds of this invention are illustrated inthe following synthetic schemes and example(s). The following schemes,examples and biological data are given for the purpose of illustratingthe invention, but not for limiting the scope or spirit of theinvention.

Synthesis of Novel Thienopyridone Compounds

Novel thienopyridinone compounds according to the present invention weresynthesized as shown below.

Novel thienopyridinone compounds of the general structure 1 may besynthesized by the coupling reaction between the amine 2 and the ester 3as shown below in Scheme 1.

More specifically, the compounds disclosed herein (where m=0 and n=1)were synthesized following the reaction sequences illustrated in Schemes2 and 3. In Step A, N-alkylation of N-Boc4-aminopiperidine (4) withalkyl halide (R₄X, X=Br or I) and potassium carbonate in DMF followed bytreatment with trifluoroacetic acid (TFA) in dichloromethane affordedthe R₄-substituted 4-aminopiperidine bis-TFA salts 2a. In generalstructure 1, R₁ and R₂ may include H; R₃ may include ethyl or isopropyl,as well as Me, Et, n-Pr, i-Pr, n-Bu, i-Bu. R₄ may include Me, Et, n-Pr,i-Pr, CH₂-cyclopropyl, n-Bu, i-By, s-Bu, n-pentyl, benzyl, phenethyl,N-3-hydroxypropyl, N-4-hydroxybutyl, N-2-hydroxypropyl, orN-5-hydroxypentyl.

In Step B, reductive alkylation of substituted or unsubstituted2-aminothiophene-3-carboxylate (6) with an aldehyde, a ketone or adimethoxy ketal yielded the alkylated product 7. In Step C, 7 wasconverted to the ester intermediate 3 in a two-step sequence: amideformation with ethyl 3-chloro-3-oxopropionate and triethylamine followedby intramolecular condensation reaction in the presence of sodiummethoxide. In Step D, the ester 3, upon heating at reflux in xylene,reacted with 2a in the presence of diisopropylethylamine afforded 1a.

-   -   Step B: Aldehyde, ketone or dimethyl ketal, NaBH(OAc)₃, CH₂Cl₂,        TFA, AcOH; Step C: ClC(═O)CH₂CO₂Et, Et₃N, CH₂Cl₂, then NaOMe,        MeOH; Step D: 2a, i-Pr₂NEt, xylene, reflux

EXPERIMENTAL Example 16,7-Dihydro-N-(1-ethylpiperidin-4-yl)-4-hydroxy-7-isopropyl-6-oxothieno[2,3-b]pyridine-5-carboxamidehydrochloride salt

Step A: Preparation of 1-ethylpiperidin-4-amine

Ethyl iodide (0.18 mL, 2.3 mmol) was added to a suspension ofN-Boc-4-aminopiperidine (0.5 g, 2.5 mmol) and potassium carbonate (0.69g, 4.6 mmol) in DMF (10 mL). The reaction mixture was stirred for 16 hand concentrated under reduced pressure. The residue was dissolved inwater and extracted with ether; the extract was washed with water, driedover anhydrous sodium sulfate and concentrated under reduced pressure toyield an off-white solid (0.53 g). This solid was treated withtrifluoroacetic acid (5 mL) in dichloromethane (10 mL) for 2 h. Thereaction mixture was concentrated under reduced pressure; the residuewas co-evaporated with hexane to remove excess trifluoroacetic acid togive the title compound as a light brown oil.

Step B: Preparation of methyl 2-(isopropylamino)thiophene-3-carboxylate

To a solution of methyl 2-aminothiophene-3-carboxylate (1.76 kg, 11.2mol) in glacial acetic acid (1.34 kg, 22.3 mol) and dichloromethane (8L) were added trifluoroacetic acid (17.8 g, 156 mmol),2,2-dimethoxypropane (6.83 kg, 65.6 mmol) and sodiumtriacetoxyborohydride (3.9 kg, 18.4 mol). The reaction mixture wasstirred for 18 h at room temperature, quenched with saturated aqueouspotassium carbonate solution (13.5 L) over 3 h and diluted with water(21 L). The organic layer was collected and the aqueous layer wasextracted with dichloromethane (2×6 kg). The combined extracts werewashed with aqueous sodium chloride solution (10 kg) and concentratedunder reduced pressure to afford a dark black-red liquid (2.4 kg). Thisresidue was purified on a 15-kg silica gel flash chromatography columneluted with 3% ethyl acetate-heptane to afford the title compound as aslightly yellow liquid.

¹H NMR (400 MHz, CDCl₃): δ 7.00 (d, 1 H, 6.15 (d, 1 H, 3.80 (s, 3 H,3.51 (m, 1 H, 1.30 (d, 6 H.

Step C: Preparation of methyl6,7-dihydro-4-hydroxy-7-isopropyl-6-oxothieno-[2,3-b]pyridine-5-carboxylate

To a solution of methyl 2-(isopropylamino)thiophene-3-carboxylate (3.50g, 17.6 mmol) in dichloromethane (50 mL) at 0° C. were addedtriethylamine (5.33 g, 52.8 mmol) followed by ethyl3-chloro-3-oxopropionate (3.96 g, 26.3 mmol). The reaction mixture waswarmed to room temperature, stirred for 2 h, concentrated and dissolvedin ethyl acetate. This solution was washed with water, dried overanhydrous sodium sulfate and concentrated to afford a dark red oilyresidue (3.50 g). To a solution of this residue in methanol (40 mL) atroom temperature were added freshly cut pieces of sodium metal (0.77 g,33.5 mmol) in portions so as to allow for a gentle reflux. After theaddition was complete, the reaction mixture was heated at reflux for 18h, cooled to room temperature and concentrated. The residue wasdissolved in water; the resulting solution was washed withdichloromethane, acidified with concentrated hydrochloric acid andextracted with ethyl acetate. The extract was washed with water, driedover anhydrous sodium sulfate and concentrated. The residual solid wasrecrystallized from ether to afford the title compound as an off-whitesolid (1.92 g, 41% yield).

¹H NMR (400 MHz, CDCl₃): δ 13.84 (s, 1 H, 7.33 (d, 1 H, 6.91 (d, 1 H,4.83 (br, 1 H, 4.01 (s, 3 H, 1.63 (d, 6 H.

Step D: Preparation of6,7-dihydro-N-(1-ethylpiperidin-4-yl)-4-hydroxy-7-isopropyl-6-oxothieno[2,3-b]pyridine-5-carboxamide

A solution of methyl6,7-dihydro-4-hydroxy-7-isopropyl-6-oxothieno-[2,3-b]pyridine-5-carboxylate(0.22 g, 0.82 mmol), 1-ethylpiperidin-4-amine (0.44 g, 1.24 mmol) anddiisopropylethylamine (0.35 mL, 2.48 mmol) in xylene (3 mL) was heatedat 120° C. for 2 h. The reaction mixture was cooled to room temperature,washed with water and concentrated under reduced pressure. The residuewas purified by silica gel flash column chromatography eluted with 3%methanol-dichloromethane to give the title compound (0.20 g, 67% yield)as an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 10.34 (br s, 1 H, 7.37(d, 1 H, 6.95 (d, 1 H, 4.01 (m, 2 H, 3.03 (m, 2 H, 2.63 (d, 2 H, 2.41(m, 2 H, 2.12 (d, 2 H, 1.81 (q, 2 H, 1.62 (d, 6 H, 1.18 (t, 3 H; MS: m/e364 (M+H⁺).

Example 26,7-Dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(1-propylpiperidin-4-yl)thieno[2,3-b]pyridine-5-carboxamide

The title compound was synthesized in a similar manner to that outlinedfor Example 1 except that ethyl iodide was replaced by propyl iodide inStep A.

¹H NMR (400 MHz, CDCl₃): δ 10.30 (br s, 1 H, 7.40 (d, 1 H, 6.98 (d, 1 H,4.00 (br, 1 H, 2.95 (m, 2 H, 2.60-1.50 (m, 10 H, 1.60 (d, 6 H, 0.98 (t,3 H; MS: m/e 378 (M+H⁺).

Example 3N-(1-Butylpiperidin-4-yl)-6,7-dihydro-4-hydroxy-7-isopropyl-6-oxothieno[2,3-b]pyridine-5-carboxamide

The title compound was synthesized in a similar manner to that outlinedfor Example 1 except that ethyl iodide was replaced by butyl iodide inStep A.

¹H NMR (400 MHz, CDCl₃): δ 10.25 (br s, 1 H, 7.37 (d, 1 H, 6.94 (d, 1 H,3.96 (m, 2 H, 2.85 (m, 2 H, 2.35 (dd, 2 H, 2.17 (t, 2 H, 2.02 (d, 2 H,1.73-1.61 (m, 7 H, 1.49 (m, 2 H, 1.34 (m, 2 H, 0.92 (t, 3 H; MS: m/e 392(M+H⁺).

Example 46,7-Dihydro-4-hydroxy-N-(1-(3-hydroxypropyl)piperidin-4-yl)-7-isopropyl-6-oxothieno[2,3-b]pyridine-5-carboxamide

The title compound was synthesized in a similar manner to that outlinedfor Example 1 except that ethyl iodide was replaced by 3-iodopropan-1-olin Step A.

¹H NMR (400 MHz, CDCl₃): δ 10.27 (br s, 1 H, 7.37 (d, 1 H, 6.94 (d, 1 H,3.98 (br, 1 H, 3.82 (t, 2 H, 3.00 (m, 2 H, 2.64 (t, 2 H, 2.20 (m, 2 H,2.04 (d, 2 H, 1.76-1.62 (m, 10 H; MS: m/e 394 (M+H⁺).

Example 5N-(1-(Cyclopropylmethyl)piperidin-4-yl)-6,7-dihydro-4-hydroxy-7-isopropyl-6-oxothieno[2,3-b]pyridine-5-carboxamide

The title compound was synthesized in a similar manner to that outlinedfor Example 1 except that ethyl iodide was replaced by cyclopropylmethylbromide in Step A.

¹H NMR (400 MHz, CDCl₃): δ 10.50 (br s, 1 H, 7.39 (d, 1 H, 6.99 (d, 1 H,4.10 (br, 1 H, 3.91-3.80 (m, 1 H, 2.98-2.30 (m, 4 H, 2.20 (d, 2 H,1.83-1.52 (m, 4 H, 1.60 (d, 6 H, 0.84-0.80 (m, 1 H, 0.60-0.30 (m, 2 H,0.20 (m, 2 H; MS: m/e 390 (M+H⁺).

Example 66,7-Dihydro-4-hydroxy-N-(1-isobutylpiperidin-4-yl)-7-isopropyl-6-oxothieno[2,3-b]pyridine-5-carboxamide

The title compound was synthesized in a similar manner to that outlinedfor Example 1 except that ethyl iodide was replaced by isobutyl iodidein Step A.

¹H NMR (400 MHz, CDCl₃): δ 10.27 (br s, 1 H, 7.39 (d, 1 H, 6.98 (d, 1 H,4.00 (br, 1 H, 2.93 (d, 2 H, 2.60-1.50 (m, 8 H, 1.60 (d, 6 H, 1.24 (m, 1H, 0.90 (d, 6 H; MS: m/e 392 (M+H⁺).

Example 76,7-Dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(1-phenethylpiperidin-4-yl)thieno[2,3-b]pyridine-5-carboxamide

The title compound was synthesized in a similar manner to that outlinedfor Example 1 except that ethyl iodide was replaced by phenethyl bromidein Step A.

¹H NMR (400 MHz, CDCl₃): δ 10.28 (br s, 1 H, 7.37 (d, 1 H, 7.31-7.26 (m,2 H, 7.23-7.19 (m, 3 H, 6.94 (d, 1 H, 3.99 (m, 1 H, 2.93 (d, 2 H, 2.82(dd, 2 H, 2.63 (dd, 2 H, 2.29 (t, 2 H, 2.05 (d, 2 H, 1.76-1.62 (m, 8 H;MS: m/e 440 (M+H⁺).

Example 86,7-Dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(1-pentylpiperidin-4-yl)thieno[2,3-b]pyridine-5-carboxamide

The title compound was synthesized in a similar manner to that outlinedfor Example 1 except that ethyl iodide was replaced by pentyl iodide inStep A.

¹H NMR (400 MHz, CDCl₃): δ 10.23 (br s, 1 H, 7.36 (d, 1 H, 6.93 (d, 1 H,3.95 (m, 1 H, 2.84 (m, 2 H, 2.32 (m, 2 H, 2.19-1.93 (m, 4 H, 1.72-1.60(m, 8 H, 1.53-1.43 (m, 2 H, 1.36-1.22 (m, 4 H, 0.89 (t, 3 H; MS: m/e 406(M+H⁺).

Example 96,7-Dihydro-7-ethyl-4-hydroxy-6-oxo-N-(1-propylpiperidin-4-yl)thieno[2,3-b]pyridine-5-carboxamide

The title compound was synthesized in a similar manner to that outlinedfor Example 1 except that ethyl iodide was replaced with propyl iodidein Step A and that 2,2-dimethoxypropane was replaced with acetaldehydewithout the use of trifluoroacetic acid in Step B.

¹H NMR (400 MHz, CDCl₃): δ 10.20 (br s, 1 H, 7.36 (d, 1 H, 6.95 (d, 1 H,4.15 (q, 2 H, 3.96 (m, 1 H, 2.85 (m, 2 H, 2.32 (m, 2 H, 2.20 (t, 2 H,2.03 (m, 2 H, 1.72 (m, 2 H, 1.53 (m, 2 H, 1.40 (t, 3 H, 0.89 (t, 3 H;MS: m/e 364 (M+H⁺).

Example 106,7-Dihydro-7-ethyl-4-hydroxy-N-(1-(3-hydroxypropyl)piperidin-4-yl)-6-oxo-thieno[2,3-b]pyridine-5-carboxamide

The title compound was synthesized in a similar manner to that outlinedfor Example 1 except that ethyl iodide was replaced with3-iodopropan-1-ol in Step A and that 2,2-dimethoxypropane was replacedwith acetaldehyde without the use of trifluoroacetic acid in Step B.

¹H NMR (400 MHz, CDCl₃): δ 10.20 (br s, 1 H, 7.36 (d, 1 H, 6.95 (d, 1 H,4.15 (q, 2 H, 3.96 (m, 1 H, 3.00 (m, 2 H, 2.82 (t, 2 H, 2.64 (t, 2 H,2.20 (m, 2 H, 2.03 (m, 2 H, 1.72-1.62 (m, 4 H, 1.40 (t, 3 H; MS: m/e 380(M+H⁺).

Biological Activity of Thienopyridinone Derivatives

Compounds of the invention synthesized above and their binding affinityto 5-HT_(4e) receptors was determined. The biological activity of thenovel thienopyridone derivatives is shown in Table 1.

TABLE 1 Biological Activity of novel thienopyridinone derivatives in5-HT4e receptor assay Example Chemical Structure Chemical Name K_(i) vs5-HT_(4e) 1

6,7-Dihydro-N-(1-ethylpiperidin-4-yl)-4-hydroxy-7-isopropyl-6-oxothieno[2,3-b]pyridine-5-carboxamide81 nM 2

6,7-Dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(1-propylpiperidin-4-yl)thieno[2,3-b]pyridine-5-carboxamide33 nM 3

N-(1-Butylpiperidin-4-yl)-6,7-dihydro-4-hydroxy-7-isopropyl-6-oxothieno[2,3-b]pyridine-5-carboxamide47 nM 4

6,7-Dihydro-4-hydroxy-N-(1-(3-hydroxypropyl)piperidin-4-yl)-7-isopropyl-6-oxothieno[2,3-b]pyridine-5-carboxamide31 nM 5

N-(1-(Cyclopropylmethyl)piperidin-4-yl)-6,7-dihydro-4-hydroxy-7-isopropyl-6-oxothieno[2,3-b]pyridine-5-carboxamide62 nM 6

6,7-Dihydro-4-hydroxy-N-(1-isobutylpiperidin-4-yl)-7-isopropyl-6-oxothieno[2,3-b]pyridine-5-carboxamide220 nM  7

6,7-Dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(1-phenethylpiperidin-4-yl)thieno[2,3-b]pyridine-5-carboxamide100 nM  8

6,7-Dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(1-pentylpiperidin-4-yl)thieno[2,3-b]pyridine-5-carboxamide47 nM 9

6,7-Dihydro-7-ethyl-4-hydroxy-6-oxo-N-(1-propylpiperidin-4-yl)thieno[2,3-b]pyridine-5-carboximide31 nM 10

6,7-Dihydro-7-ethyl-4-hydroxy-N-(1-(3-hydroxypropyl)piperidin-4-yl)-6-oxothieno[2,3-b]pyridine-5-carboxamide100 nM 

These novel compounds accordingly are expected to be useful as activeand selective 5-HT₄ receptor modulators, e.g., in the treatment of awide variety of clinical conditions including Alzheimer's disease,cognition disorders, irritable bowel syndrome, Parkinson's disease,nausea, emesis, vomiting, prokinesia, gastroesophageal reflux disease,nonulcer dyspepsia, depression, anxiety, urinary incontinence, migraine,arrhythmia, atrial fibrillation, ischemic stroke, gastritis, gastricemptying disorders, feeding disorders, gastrointestinal disorders,constipation, erectile dysfunction, respiratory depression, which arecharacterized by serotonin excess or absence, e.g., serotoninergichypofunction or hyperfunction.

Equivalents

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures described herein. Such equivalents are considered tobe within the scope of the invention and are covered by the followingclaims. Various substitutions, alterations, and modifications may bemade to the invention without departing from the spirit and scope of theinvention as defined by the claims. Other aspects, advantages, andmodifications are within the scope of the invention. The contents of allreferences, issued patents, and published patent applications citedthroughout this application are hereby incorporated by reference. Theappropriate components, processes, and methods of those patents,applications and other documents may be selected for the invention andembodiments thereof.

1. A compound having the formula

wherein R₁ is ethyl or isopropyl; and R₂ is an optionally substitutedalkyl group selected from the group consisting of ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, methylcyclopropyl,isopropanol, and phenylethyl; and pharmaceutically acceptable saltsand/or esters thereof.
 2. The compound of claim 1, wherein saidpharmaceutically acceptable salt is selected from the group consistingof hydrochloride, maleate, citrate, fumarate, succinate, tartarate,mesylate, sodium, potassium, magnesium, and calcium salts.
 3. Apharmaceutical composition comprising the compound of claim 1 and apharmaceutically acceptable carrier. 4.6,7-dihydro-N-(1-ethylpiperidin-4-yl)-4-hydroxy-7-isopropyl-6-oxothieno[2,3-b]pyridine-5-carboxamide, and pharmaceutically acceptable saltsthereof. 5.6,7-Dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(1-propylpiperidin-4-yl)thieno[2,3-b]pyridine-5-carboxamide,and pharmaceutically acceptable salts thereof. 6.N-(1-Butylpiperidin-4-yl)-6,7-dihydro-4-hydroxy-7-isopropyl-6-oxothieno[2,3-b]pyridine-5-carboxamide,and pharmaceutically acceptable salts thereof. 7.6,7-Dihydro-4-hydroxy-N-(1-(3-hydroxypropyl)piperidin-4-yl)-7-isopropyl-6-oxothieno[2,3-b]pyridine-5-carboxamide,and pharmaceutically acceptable salts thereof. 8.N-(1-(Cyclopropylmethyl)piperidin-4-yl)-6,7-dihydro-4-hydroxy-7-isopropyl-6-oxothieno[2,3-b]pyridine-5-carboxamide,and pharmaceutically acceptable salts thereof. 9.6,7-Dihydro-4-hydroxy-N-(1-isobutylpiperidin-4-yl)-7-isopropyl-6-oxothieno[2,3-b]pyridine-5-carboxamide,and pharmaceutically acceptable salts thereof. 10.6,7-Dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(1-phenethylpiperidin-4-yl)thieno[2,3-b]pyridine-5-carboxamide,and pharmaceutically acceptable salts thereof. 11.6,7-Dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(1-pentylpiperidin-4-yl)thieno[2,3-b]pyridine-5-carboxamide,and pharmaceutically acceptable salts thereof. 12.6,7-Dihydro-7-ethyl-4-hydroxy-6-oxo-N-(1-propylpiperidin-4-yl)thieno[2,3-b]pyridine-5-carboxamide,and pharmaceutically acceptable salts thereof. 13.6,7-Dihydro-7-ethyl-4-hydroxy-N-(1-(3-hydroxypropyl)piperidin-4-yl)-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,and pharmaceutically acceptable salts thereof.